P1123: EARLY CTDNA CLEARANCE AFTER CAR T-CELL INFUSION PREDICTS OUTCOME IN PATIENTS WITH LARGE B-CELL LYMPHOMA: RESULTS FROM ALYCANTE, A PHASE 2 LYSA STUDY
Authors: Marie-Helene Delfau-Larue, Lucie Gomes, Guillaume Cartron, Franck Morschhauser, Francois-Xavier Gros, Thomas Gastinne, Lucie Oberic, Emmanuel Bachy, Pierre Feugier, Rémy Duléry, Cedric Menard, Celine Pangault, Alexis Claudel, Cathy Quelen, Cedric Portugues, Pierre-Julien Viailly, Francois Lemonnier, Emmanuel Itti, Clément Bailly, Camille Laurent, Roch Houot
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: CAR T-cells have significantly improved the outcome of patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). However, more than half of the patients will fail to obtain a prolonged remission after CAR T-cell therapy, resulting in a poor prognosis. Early identification of these patients would allow early intervention to improve their outcome. Circulating tumor DNA (ctDNA) assessment is a promising tool to monitor early response in cancer, including LBCL, but few data are available regarding ctDNA monitoring after treatment with CD19 CAR T-cells. Aims: To monitor ctDNA before and after CAR T-cell infusion and correlate the results with clinical outcome in the ALYCANTE trial Methods: Patients' samples were prospectively collected in the ALYCANTE trial, an open-label, phase 2 study (NCT04531046), designed to evaluate the efficacy and safety of axi-cel in 62 patients with R/R LBCL not intended for autologous stem cell transplantation after 1 prior line of therapy. DNA was extracted from 2 to 4ml of plasma collected in streck tubes. Libraries were constructed by capturing 129 Kilobases (Kb) (Agilent, Kit XTHS2) corresponding to 90Kb of the 269 most frequently mutated coding exons in BCL and 39 Kb of the 36 most frequent source of phased variants in LBCL non-coding regions (Kurtz, Nat biot 2021). Bioinformatics analysis were carried out in the framework of the French Connect consortium using GenerateReports pipeline for primary and secondary analysis. UMI-VarCal was used for bioinformatics variant calling and phased variant annotation using Unique Molecular Identifiers (UMI). Concentrations of ctDNA were expressed as haploid genome equivalents by volume (hGE/mL), calculated by mean variant allelic frequency (VAF) x concentration of cell free DNA (cfDNA). ctDNA was measured at leukapheresis, after bridging/before lymphodepletion, at time of CAR T-cell infusion (D0) and at day 14 (D14), month 1 (M1), 3, 6, 9, and 12 after infusion. These results were correlated with clinical outcome. Results: A mutational profile could be identified from ctDNA in 88% (55/62) of patients at the time of leukapheresis (n= 54) or after bridging (n=1). Identification of variants in the tumor biopsy with the same panel confirmed the absence of detectable ctDNA in 4 patients. Tumor biopsy was not available in the 3 remaining patients who were considered free of ctDNA. A median of 85 variants (range, 1-707) was detected in positive patients. Median ctDNA load was 124 hGE/ml (range, 3.6 to 6803) at leukapheresis and only slightly lower after bridging therapy with a median of 67 hEG/ml (2 to 17354. Only 2/55 (4%) patients experienced ctDNA clearance after bridging therapy. To date, we were able to study the clinicobiological correlations for the first 40 patients (out of 62 patients) included in the ALYCANTE study. Early ctDNA evaluation was performed in 38/40 (95%) patients: at D14 only (n=2), at D14 and M1 (n=34), and at M1 only (n=2). For patients with D14 and M1 evaluation, the results were concordant in 32/34 (94%) patients, either both positive (n=19) or both negative (n=13). A negative ctDNA at D14 (n=14/36) or at M1 (n=16/36) was associated with a complete metabolic response at M3 in 93% (13/14, p= 0.03) and 94% (15/16, p=0.009) of cases, respectively. With a median follow-up of 10 months, the median progression free survival was not reached for D14 and M1 negative ctDNA vs 7.6 months for positive D14 and 5.8 months for positive M1(+) ctDNAs. (Figure 1). Summary/Conclusion: These preliminary results suggest that early clearance of ctDNA at day 14 and month 1 post-infusion is predictive of outcome after CAR T-cell therapy in patients with R/R LBCL. An update of these results on 62 patients and with a longer follow-up will be presented at the meeting.Keywords: Diffuse large B cell lymphoma, ctDNA, DLBCL, CAR-T